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2007 Grant - R. Li

Studies on Estrogen and DNA Repair in an APP Transgenic Mouse Model

Rena Li, M.D., Ph.D.
Sun Health Research Institute
Sun City, Arizona

2007 Investigator-Initiated Research Grant

DNA harbors the genetic code that is essential for life as we know it. But despite its importance, DNA is not a very stable molecule. It is estimated that the DNA in each neuron undergoes 20,000 chemical changes daily. Such alteration would be catastrophic if there were not a host of DNA repair enzymes ready to correct any errors in the code and ensure that the template for life remains accurate. However, these repair mechanisms are not infallible, and changes to DNA do accumulate over time. The slow accumulation of DNA damage is thought to be linked to age-related diseases such as Alzheimer's disease.

Rena Li, Ph.D., and colleagues recently found that levels of DNA repair proteins are lower in people with Alzheimer's disease and that these reductions correlate with increased level of amyloid plaques and neurofibrillary tangles, protein aggregates that are hallmarks of the disease. They also found in studies with mice that loss of estrogen accelerates the accumulation of beta-amyloid, the major component of amyloid plaques, and that loss of estrogen causes neuronal death.

The researchers plan to investigate if loss of estrogen and overproduction of beta-amyloid, the major constituent of amyloid plaques, are related to DNA damage. They will examine if DNA repair protein levels are lower in mice that produce vast excesses of beta-amyloid. They will study the role of estrogen in DNA repair and cell death by studying a mouse that both produces excess beta-amyloid and is depleted of naturally occurring estrogen. And they will determine if DNA repair can be improved in mouse models of Alzheimer's disease by administering estrogen to the animals. The studies will help researchers better understand the pathology of the disease and may reveal new strategies for diagnosis and treatment.